CONTROL OF CANCER METABOLISM

Dr. David Finlay

Dr. David Finlay
Phone: +353-1-8963564
Fax: +353-1-6772400
Email: finlayd@tcd.ie
Location: 5th Floor, Biomedical Sciences Institute

Research Interests

It is widely believed that cancer cells hijack cellular systems that are normally tightly regulated and used in a specific cellular context, in order to facilitate their aberrant growth and survival. It is on this premise that my research studies the mechanisms regulating the metabolism of certain untransformed primary cell subsets. Various immune subsets dramatically up-regulate their cellular metabolism in response to physiological stimuli. The activation of CD8+ T cells, dendritic cells (DCs) and macrophages induces substantial increases glucose uptake and glycolysis, and also lipid metabolism that is required to meet the significant metabolic demands of proliferation and effector functions. Thus, activated CD8+ T cells, DCs and macrophages display many of the metabolic hallmarks of cancer cells. Increased glucose uptake and metabolism through the glycolytic pathway is a fundamental hallmark of cancer and was first noted over 80 years ago by Oto Warburg (termed 'The Warburg Effect). Through a detailed understanding of the systems controlling the metabolic changes in activated CD8+ T cells, DCs and macrophages my research aims to gain insight to the mechanisms likely used in various haematological malignancies such as acute myeloid leukaemia (AML). Various mouse models of haematological malignancies can then be used validate these mechanisms in tumour cells and to identify potential targets for cancer therapy.

Following this strategy my research has identified a key role for the transcription factor Arnt in promoting elevated glucose metabolism in activated CD8+ T cells. Using genetically modified mice we specifically deleted the Arnt gene in T cells (Arnt ^flox/flox CD4Cre mice) and demonstrated that loss of Arnt function in activated CD8+ T cells strongly inhibits glucose uptake and glycolsyisxz. Glucose metabolism is also linked to the regulation of apoptosis and interfering with Arnt function in activated CD8+ T cells also sensitizes these cells to apoptosis. This data identifies Arnt as a potential novel therapeutic target for highly glycolytic haematological malignancies such as Acute Myeloid Leukaemia. I aim to investigate the role of Arnt in human AML etiology in collaboration with clinical colleagues at St. James Hospital, Trinity College Dublin (Drs. Eiblin Conneally and Catherine Flynn) and Ninewells Hospital, University of Dundee (Dr Gavin Preston).

Key Research Questions:

What are the signalling pathways that regulate the elevated cellular glucose and lipid metabolism evident in activated T lymphocytes, dendritic cells and macrophages and how does this metabolism impact on the function of these cells?

Are these signalling pathways responsible for the metabolic changes associated with haematological malignancy? Do these pathways represent good targets for cancer drug development?

Funding

Tenovus Scotland - Small Research Grant

Collaborators

Dr Gavin Preston - Ninewells Hospital, University of Dundee, Scotland.
Dr Eibhlin Conneally - St. James Hospital, Trinity College Dublin.
Dr. Catherine Flynn - St. James Hospital, Trinity College Dublin.
Prof. Luke O'Neill - School of Biochemistry and Immunology, Trinity College Dublin.
Prof Doreen Cantrell - School of Life Sciences, University of Dundee, Scotland.

Recent Publications by David Finlay and the Control of Cancer Metabolism group

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